The urgency in identifying countermeasures against biologic threats cannot be overstated. Biological weapons are real threats today and new vaccines and other countermeasures were needed "yesterday" to help protect the public and soldiers in high-risk areas. Vaccines offer the "best" countermeasure, but few exist for many of the well-known threats. The development of vaccines is disease specific; thus, the time and expense spent on a single vaccine development will need to be repeated for each disease-causing agent. As such, there is a need to develop other countermeasures that are not disease-agent specific and protect against a broad and, many times, largely unforeseen spectrum of pathogens-the role of the innate immune system. This project is focused on identifying for clinical use, oral adjuvants that enhance innate immunity against the causative agent of Q-fever~Cox/e//a bumetii. The following hypothesis will be tested in this project: toll-like receptor 2 (TLR2) agonists increase macrophage killing of C. bumetii and increase resistance to infection in vivo. The ultimate goal is to develop orally active adjuvants that can be used therapeutically or prophylactically to increase human resistance to C. bumetii induced pneumonia. The following specific aims will be pursued. Specific Aim 1: Determine effect of TLR2 agonists on in vitro killing of avirulent and virulent C. bumetii by macrophages from resistant and susceptible mice. Specific Aim 2: Determine mechanism of action of TLR2 agonists, or other agonists defined in Aim 1, in increasing macrophage killing of C. bumetii. Specific Aim 3: Determine effect of TLR2 agonist, or other agonists defined in the experiments under Aims 1 and 2, on host resistance to in vivo challenge with avirulent C. bumetii. Project interactions: This project is made possible by participation in the RCE and involves direct interactions with the work being done by Dr. Harmsen on host/pathogen interactions, Dr. Minnick on bacterial pathogenesis and Dr. Pascual on vaccine development. It also complements the efforts on adjuvant therapy for pulmonary virus infections being pursued at USU and the studies of innate host responses against Burkholderia being done at CSU. This projects will also involve extensive interactions wjth the bacteriology CORE A.